Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
On the other hand, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant by Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93, p 13152-13157. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Some integrase inhibitors have recently been reported, for example, 1,3-dioxo butenoic acid group or 1,3-propandione group described in WO99/50245, WO99/62520, WO99/62897, WO99/62513, WO00/39086 and WO01/00578.
Additionally, benzimidazole derivatives, anti-platelet agents are described in Chem. Pharm. Bull. 42(3) 560-569 (1994). They have similar structures to those of the present invention compounds.
WO98/45269 and J. Med. Chem. 2000, 43, 1533-1540 describe the following compounds with inhibitory activity against HIV integrase.
Wherein RB′ is hydroxy or alkoxy, Z2′ is alkylene or alkenylene, R1′ is optionally substituted aryl or optionally substituted heteroaryl.
Furthermore, in U.S. Pat. No. 3,113,135, 5-benzyl-7-acetyl-8-hydroxyquinoline and 5-phenyl-7-acetyl-8-hydroxyquinoline are described.
Under the above circumstance, the development of a novel integrase inhibitor has been desired.